Long-term treatment with the type 2 diabetes drug metformin improves health and longevity of male mice when started at middle age, reports an international team of scientists led by researchers at the National Institute on Aging (NIA), part of the National Institutes Health. The study, which tested two doses of the drug in the male mice, found the higher dose to be toxic in the animals. Scientists emphasized that considerably more research is needed before the implications of metformin for healthy aging are known for humans.

The study, headed by Rafael de Cabo, Ph.D., of the NIA’s Intramural Research Program, was published in the July 30, 2013 issue of Nature Communications.

“There is increasing interest in exploring how drugs for one use might be repurposed for another,” notes Richard J. Hodes, M.D., director of the NIA. “It is exciting to discover that a drug already known to be safe and effective in humans might be further studied for a possible, alternate use for healthy aging.”

Prescribed since the 1960s to treat type 2 diabetes, metformin is known to enhance insulin sensitivity, prompt sugar to be converted to energy, and prevent sugar build up in the liver. It also reduces risk of health issues associated with metabolic syndrome, a condition characterized by an increased chance for heart disease and stroke, as well as type 2 diabetes.

“Aging is a driving force behind metabolic syndrome and diabetes. Given that metformin is clinically proven to alleviate symptoms of these conditions, and reduce risk of cancer, we thought perhaps it was a good candidate to study for its broader effects on health and lifespan,” said de Cabo.

Specifically, de Cabo’s research focuses on testing compounds that might mimic benefits of calorie restriction, as shown in some animal models. A significant reduction in calories causes the body to adjust how it creates and processes energy, generating a mild biological stress, which contributes to the reported health benefits. Metformin works, at least in part, by also controlling the body’s energy use and production. The study offers evidence that metformin might provide some of the positive effects of calorie restriction.

In this study, researchers found male mice on a 0.1 percent metformin treatment had a 5.83 percent increase in lifespan compared to control group mice on a standard diet with no metformin. The 1 percent metformin treatment had the opposite effect. These mice had a 14.4 percent shorter lifespan compared to the control group, likely due to kidney failure. The lower metformin dose did not seem to cause any negative effect on the renal system.

A battery of tests performed with male mice taking 0.1 percent, 1 percent or no metformin starting at middle age, revealed a clear health benefit of the 0.1 percent treatment. These mice had improved general fitness and weighed less than the control group mice, despite consuming more calories. Metformin increased their use of fat for energy. Mice on metformin tended to preserve body weight with age, a characteristic associated with increased survival in other studies. They had a lower incidence of cataracts, a common health problem in the strain of mouse. Not surprisingly, metformin prevented the onset of metabolic syndrome. It had similar effects as calorie restriction on genes in the liver and muscles, which induced longevity-associated activity in the mice. Metformin also appeared to have some antioxidant effects in the mice.

A number of compounds are being tested for their possible applications to improving health with aging. A previous study by de Cabo and colleagues found that resveratrol, present in foods like grapes and nuts, improved a number of health measures in mice, but perhaps not their longevity.

The NIA-sponsored Interventions Testing Program has studied the effects of several compounds, including metformin, resveratrol, and the immunosuppressant rapamycin, in mice. The initiative found that rapamycin extended lifespan even when fed to the mice beginning at early-old age and is looking more closely at its possible health benefits. Learning more about these and other compounds and the mechanisms underlying their effects on the body, may point the way to future aging therapies in humans.